Project Summary Aging is associated with multiple differential changes in the brain, and understanding the neural mechanisms that drive age-related cognitive declines is a matter of great importance. Charting the natural course of aging in healthy adults and elucidating the neural mechanism of change and their modifiers has been an overarching goal of our research work in the past two decades. The results of our studies in the past two decades confirm earlier findings of particular vulnerability in the brain regions (hippocampus, orbital?frontal cortex, entorhinal/parahippocampal cortex and cerebellum) and association white matte fibers that connect these areas. In investigating the possible mechanism underlying these changes, we found that increase in iron content (a proxy for oxidative stress) of the striatum influences shrinkage of that region and mediate changes in cognitive skill such as working memory. We also found that whereas shrinkage of age-sensitive brain regions predicts changes in important cognitive abilities, possession of better cognitive endowment at baseline predicted lesser shrinkage of one of the most important brain regions ? the prefrontal cortex, thus suggesting that in aging, the relationship between brain and cognition is reciprocal and that better cognitive abilities may act as a neuroprotective modifier of aging. In addition, we found that physiological and genetic indicators of vascular and metabolic risk as well as proneness to systemic inflammation play a role in promoting age-related brain declines. In the proposed continuation study, we will carry on collecting longitudinal data initiated at the inception of this project as it will provide us with an opportunity to examine the shape of age-related change trajectory and test the possibility of non-linear course. At the same time, we will expand the focus of our search for mechanisms of cognitive aging by turning attention to two domains whose importance in cognitive aging has been bolstered in the past decade: maintenance of subcortical and cortical myelin and preservation of the brain energy metabolism. We will conduct (for the first time) longitudinal assessment in these two domains in conjunction with continuing previously introduced measurement of brain volume, white matter microstructure and iron accumulation. We will test hypotheses pertaining to the temporal dynamics of brain and cognitive aging and will examine the lag-lead relationships between brain energy metabolisms (hypothesized as the primary instigator of neurocognitive aging), structural shrinkage, and myelin loss and iron accumulation (the main mediators of structural change). We will examine the reciprocal role of changes in the brain and age- sensitive cognitive functions as well as moderating role of vascular, metabolic and inflammatory risk factors in these relationships. It is our hope that understanding of the brain mechanisms that underpin normal cognitive aging will arm us with necessary knowledge and will aid in developing interventions aimed at mitigating age- related cognitive declines. Ultimately, we believe that this research will help to establish the normative benchmarks necessary for understanding Alzheimer?s disease and other dementias.